Project Summary/Abstract The percentage of the population afflicted by obesity has relentlessly increased over the past century in industrialized countries. This has closely tracked the development of widely available, calorically dense, highly palatable foods (fast food, candy, soda, etc). Overconsumption is a necessary component in the pathogenesis of obesity. However, the mechanisms by which the homeostatic neurocircuits regulating the balance between sensations of hunger and satiety are disrupted is not yet known. Interestingly, there is mounting evidence that the neural and hormonal signals indicating negative energy balance (e.g. ghrelin) directly increase the sensitivity of the motivational neurocircuitry. It appears that hunger may represent a state of reward sensitivity; thus, food consumption may primarily rely upon the evaluated rewarding properties of the food in question. Understanding the brain phenomena which make food seem so rewarding will allow the development of novel therapies and more targeted approaches in treatment of obesity. The lateral hypothalamus is a key mediator of cue- and reward-mediated feeding behavior and understanding its function in both reward and food acquisition will lend this insight. In this proposal, we aim to characterize, for the first time, the behavioral consequence of activating the lateral hypothalamus (LH) projections to basal forebrain nuclei (medial septum and diagonal band of broca M/D). We have identified a unique combination of both induced food consumption - indicating hunger - and preference for self-stimulation over food consumption despite being in a food deprived state -indicating it is intrinsically rewarding. Thus, we propose to elaborate and characterize on this unique phenotype. We also propose to identify the molecular identity of both the pre- and postsynaptic neurons in this circuit, with the hypothesis that lateral hypothalamic GABAergic neurons synapse on dual GABAergic and cholinergic neurons in the basal forebrain. This comprehensive study of the function of the LH?M/D circuit will be the first to report on this projection and lend further mechanistic insight into the crosstalk between hunger and reward. It will also provide the PI with substantial training and experience to become a productive and innovative psychiatrist and physician scientist in the future.